NEWS & VIEWS OSTEOARTHRITIS
Priorities for osteoarthritis research: much to be done David T. Felson
With a frustrating lack of progress in the development of treatments for osteoarthritis, EULAR has released recommendations to reorient research into this disease. These recommendations include focused attention on noncartilagenous tissues, the interaction of structures within the joint, the pathogenesis of osteoarthritic pain, new treatment strategies and early disease. Felson, D. T. Nat. Rev. Rheumatol. advance online publication 20 May 2014; doi:10.1038/nrrheum.2014.76
Osteoarthritis (OA) is the most common form of arthritis; few effective medic al treatments are available and none that have shown consistent slowing of the rate of disease. Given the failure of current treatment options to either delay or prevent OA, Conaghan and others from EULAR created a list of OA research priorities1 to push the agenda for research in this field. I review here the new directions suggested (Box 1), most of which are badly needed, and raise questions about a few of the recommendations. The committee first provided data on the immense public health and societal burden of OA in Europe.1 OA accounts for more mobility disability than any other disease. As the major cause of knee and hip replacements, of which rates have been increasing rapidly in developed countries, the costs of OA are causing financial stress to many health-care systems. The future burden of OA is likely to be even greater than the daunting current estimates because populations in developed countries are ageing, and rates of obesity— a major risk factor for OA—are increasing in almost all of them. The rates of OA in countries with emerging economies, such as China and India, are also high. Given the magnitude of the problem of OA, why does it remain unsolved? One reason is that studies over the past 10–20 years have revealed a disease that is more complex than earlier research suggested. OA is the consequence of a dynamic interaction between abnormal mechanics (loads) and inflammatory response to those loads, both of which contribute substantially to disease causation and progression. Treating inflammation in
OA is possible, but correction of the abnormal loading when it has developed over years is exceedingly challenging. Moreover, it might be impossible to develop highly effective OA treatments without addressing this mechanopathology. Another major reason why treatment development for OA has been unsuccessful is that there is a weak correlation between pain and structural abnormalities in OA, especially when those structural findings are characterized by radiography.2 As cartilage is not innervated, chondroprotective treatments might not directly alleviate pain. Iden tifying and targeting sources of pain within the joint could, therefore, be more successful than cartilage-focused approaches. In middle-aged and older persons, OA develops in senescent hyaline and fibro cartilage, 3 fragile tissues that are easily damaged perhaps by minimal trauma. This change in tissue structure occurs ‘silently’ over many years. Therefore, preventing or reversing these changes are formidable challenges. Lastly, longitudinal studies incorporating MRI scans have suggested that by the time people develop OA symptoms their disease is often far advanced structurally and might not be reversible.4 This feature is a similar problem to that of another chronic disease of ageing, Alzheimer disease, which has also been challenging to treat. The EULAR committee1 recommended research that would focus on noncartilage articular pathology, including pathology in the synovial membrane and subchondral bone and how these effects interact with cartilage to worsen the osteoarthritic process.
NATURE REVIEWS | RHEUMATOLOGY
I would add to this mixture better study of critical supportive fibrocartilaginous structures such as the meniscus and the labrum. Although successfully treating existing OA can be a challenge, there could be a unique opportunity to prevent post-injury OA as the joint sustaining a major injury usually has neither pre-existing structural abnormalities nor abnormal mechanics. In one animal model of post-injury OA,5 inflammatory processes drive much of the joint destruction. More investigation of early posttraumatic OA is needed to gauge whether anti-inflammatory treatments might prevent later disease. As suggested by the EULAR committee, 1 a more multidisciplinary approach to the investigation of OA pathogenesis is needed. This approach should incorporate an understanding of the in vivo biomechanics and the biological response to that loading to determine whether injurious responses can be abrogated either by biologic therapy and/or by alteration in loads. Furthermore, the whole joint should be the subject of these studies, not just hyaline cartilage. In addition, animal models that better replicate human OA—in that they start with an already damaged joint rather than a ‘pristine’, unaffected one—are also needed. Research Box 1 | EULAR research priorities in OA1 Tissue communication in OA ■■ Better understanding of nonarticular pathology process of joint trauma and repair ■■ Understanding of the effects of comorbidities on OA pathology Mechanisms of pain ■■ Relationship of structural pathology and pain ■■ Sources of pain in OA and how they might be targeted Treatment strategies ■■ Individualized or pathology-targeted therapy Early OA ■■ What is early OA and what determines the evolution to manifestations of the disease? Predictors of progression ■■ Studies of foot OA ■■ Performance metrics of imaging techniques and biomarkers Abbreviation: OA, osteoarthritis.
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS priority also ought to be given to better characterizing human loading during activity as any attempts at correcting mechanopathology will fail as long as the actual in vivo focal loads are not precisely characterized. The EULAR committee recommended that the OA research portfolio be expanded to include foot OA. Given the increased prevalence of OA in ageing populations, shoulder and ankle OA should be added to this list, joints believed in the past to be rarely affected by OA. Furthermore, improved understanding of the relationship between spinal disease and peripheral OA is needed as insights from one of these fields in terms of disease pathogenesis or treatment could inform the other.
‘‘
Given the magnitude of the problem of OA, why does it remain unsolved?
’’
Other recommendations from the committee, unfortunately, might be less likely to yield insights. The research community is migrating quickly to the study of those with early OA; however, by the time individuals present to physicians with knee or hip pain, structural abnormalities seen by MRI have probably been present for a long period even when radiographs were normal.4 Even this ‘early’ disease presentation might be too late for successful structural modification. Other strategies could include prevention of disease in as yet unaffected joints in a person who has initial symptoms in only one joint6 and asking persons known to be at risk of OA to adopt preventive strategies. This latter approach might work if persons with early OA had an initial bout of joint pain that was, for them, a ‘teachable moment’. Given the poor diagnostic performance of single or multiple biochemical markers in blood and urine in patients with OA versus controls, 7 it is unlikely that biomarker studies of blood or urine will yield diagnostic tests for OA. This caveat is true, in part, because these biomarkers emanate from multiple different sites in the body and characterizing one or two joints as having disease on the basis of a ‘flood’ of markers from multiple joints is not terribly valuable. Biochemical markers might ultimately be valuable as measures of treatment response
or as indicators of the burden of disease (discussed elsewhere7). On the other hand, MRI findings could be used to offer sensitive information about the degree of structural abnormalities and provide information on treatable abnormalities. Lastly, the committee advocated more studies on the progression of OA.1 Ideally, a risk factor for progression would be a modifiable target for treatment. However, there have been two systemic reviews of a large number of studies on OA progression (for instance by Chapple et al.8), and both have concluded that there are few, if any, consistently identified risk factors for dis ease progression in OA; for example, obesity has not been shown to consistently increase the risk of disease progression, although it does increase the risk of incidence in almost all studies examined. Why are risk factors for OA disease progression so hard to identify? As noted in recent work about the obesity paradox in heart disease (obesity ironically decreases the risk of subsequent events in those with heart disease), there are daunting methodological challenges to studying risk factors for disease progression. These challenges have gone under different names in the medical9 and arthritis literature,10 including index event bias and collider selection bias. The main idea is that among persons with disease, all have to have had risk factors for disease incidence to get disease and, thus, also have risk factors for disease progression. Identifying risk factors for progression is only possible if the disease sample studied includes some persons who have no risk factors for progression, but that is never the case. Differentiating the effects of these factors on the risk of progression is terribly difficult; it is easier to study risk factors for disease incidence because these studies evaluate a mixed population containing some persons without disease risk factors. The only easily identifiable risk factors for OA progression are risk factors that develop as a variable consequence of disease such as malalignment, which has been shown to be a risk factor for progression in at least one systematic review. 8 The presence of this bias suggests that only incidence studies or studies of very early disease will provide useful information about risk factors for OA progression and that pursuing large-scale
2 | ADVANCE ONLINE PUBLICATION
studies of risk factors for disease progression will probably not be fruitful in identifying new treatment targets. In summary, motivated by our lack of success in developing nonsurgical treatments for OA and the increasing burden this disease poses to our society and our patients, a EULAR committee has put forward new priorities for research that, if followed, might finally begin to yield treatments that delay progression or prevent disease. Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Suite 200, 650 Albany Street, Boston, MA 02118, USA. [email protected] Acknowledgements D.T.F. is supported by NIH grant AR47785. Competing interests The author acts as a consultant for Zimmer Knee Creations. 1.
Conaghan, P. G., Kloppenburg, M., Schett, G. & Bijlsma, J. W. Osteoarthritis research priorities: a report from a EULAR ad hoc expert committee. Ann. Rheum. Dis. http://dx.doi.org/ 10.1136/annrheumdis-2013-204660. 2. Cibere, J. et al. Association of clinical findings with pre-radiographic and radiographic knee osteoarthritis in a population-based study. Arthritis Care Res. (Hoboken) 62, 1691–1698 (2010). 3. Loeser, R. F. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 17, 971–979 (2009). 4. Sharma, L. et al. Significance of preradiographic MRI lesions in persons at higher risk for knee osteoarthritis. Arthritis Rheum. http://dx.doi.org/10.1002/art.38611. 5. Mangiapani, D. S. et al. Inhibition of Interleukin‑1 prevents post-traumatic arthritis following articular fracture in the mouse knee [abstract 711]. Presented at the ORS 2012 Annual Meeting. 6. Jones, R. K. et al. A new approach to prevention of knee osteoarthritis: reducing medial load in the contralateral knee. J. Rheumatol. 40, 309–315 (2013). 7. Felson, D. T. The current and future status of biomarkers in osteoarthritis. J. Rheumatol. (in press). 8. Chapple, C. M., Nicholson, H., Baxter, G. D. & Abbott, J. H. Patient characteristics that predict progression of knee osteoarthritis: a systematic review of prognostic studies. Arthritis Care Res. (Hoboken) 63, 1115–1125 (2011). 9. Dahabreh, I. J. & Kent, D. M. Index event bias as an explanation for the paradoxes of recurrence risk research. JAMA 305, 822–823 (2011). 10. Zhang, Y. et al. Methodologic challenges in studying risk factors for progression of knee osteoarthritis. Arthritis Care Res. (Hoboken) 62, 1527–1532 (2010).
www.nature.com/nrrheum © 2014 Macmillan Publishers Limited. All rights reserved
Priorities for osteoarthritis research: much to be done David T. Felson
With a frustrating lack of progress in the development of treatments for osteoarthritis, EULAR has released recommendations to reorient research into this disease. These recommendations include focused attention on noncartilagenous tissues, the interaction of structures within the joint, the pathogenesis of osteoarthritic pain, new treatment strategies and early disease. Felson, D. T. Nat. Rev. Rheumatol. advance online publication 20 May 2014; doi:10.1038/nrrheum.2014.76
Osteoarthritis (OA) is the most common form of arthritis; few effective medic al treatments are available and none that have shown consistent slowing of the rate of disease. Given the failure of current treatment options to either delay or prevent OA, Conaghan and others from EULAR created a list of OA research priorities1 to push the agenda for research in this field. I review here the new directions suggested (Box 1), most of which are badly needed, and raise questions about a few of the recommendations. The committee first provided data on the immense public health and societal burden of OA in Europe.1 OA accounts for more mobility disability than any other disease. As the major cause of knee and hip replacements, of which rates have been increasing rapidly in developed countries, the costs of OA are causing financial stress to many health-care systems. The future burden of OA is likely to be even greater than the daunting current estimates because populations in developed countries are ageing, and rates of obesity— a major risk factor for OA—are increasing in almost all of them. The rates of OA in countries with emerging economies, such as China and India, are also high. Given the magnitude of the problem of OA, why does it remain unsolved? One reason is that studies over the past 10–20 years have revealed a disease that is more complex than earlier research suggested. OA is the consequence of a dynamic interaction between abnormal mechanics (loads) and inflammatory response to those loads, both of which contribute substantially to disease causation and progression. Treating inflammation in
OA is possible, but correction of the abnormal loading when it has developed over years is exceedingly challenging. Moreover, it might be impossible to develop highly effective OA treatments without addressing this mechanopathology. Another major reason why treatment development for OA has been unsuccessful is that there is a weak correlation between pain and structural abnormalities in OA, especially when those structural findings are characterized by radiography.2 As cartilage is not innervated, chondroprotective treatments might not directly alleviate pain. Iden tifying and targeting sources of pain within the joint could, therefore, be more successful than cartilage-focused approaches. In middle-aged and older persons, OA develops in senescent hyaline and fibro cartilage, 3 fragile tissues that are easily damaged perhaps by minimal trauma. This change in tissue structure occurs ‘silently’ over many years. Therefore, preventing or reversing these changes are formidable challenges. Lastly, longitudinal studies incorporating MRI scans have suggested that by the time people develop OA symptoms their disease is often far advanced structurally and might not be reversible.4 This feature is a similar problem to that of another chronic disease of ageing, Alzheimer disease, which has also been challenging to treat. The EULAR committee1 recommended research that would focus on noncartilage articular pathology, including pathology in the synovial membrane and subchondral bone and how these effects interact with cartilage to worsen the osteoarthritic process.
NATURE REVIEWS | RHEUMATOLOGY
I would add to this mixture better study of critical supportive fibrocartilaginous structures such as the meniscus and the labrum. Although successfully treating existing OA can be a challenge, there could be a unique opportunity to prevent post-injury OA as the joint sustaining a major injury usually has neither pre-existing structural abnormalities nor abnormal mechanics. In one animal model of post-injury OA,5 inflammatory processes drive much of the joint destruction. More investigation of early posttraumatic OA is needed to gauge whether anti-inflammatory treatments might prevent later disease. As suggested by the EULAR committee, 1 a more multidisciplinary approach to the investigation of OA pathogenesis is needed. This approach should incorporate an understanding of the in vivo biomechanics and the biological response to that loading to determine whether injurious responses can be abrogated either by biologic therapy and/or by alteration in loads. Furthermore, the whole joint should be the subject of these studies, not just hyaline cartilage. In addition, animal models that better replicate human OA—in that they start with an already damaged joint rather than a ‘pristine’, unaffected one—are also needed. Research Box 1 | EULAR research priorities in OA1 Tissue communication in OA ■■ Better understanding of nonarticular pathology process of joint trauma and repair ■■ Understanding of the effects of comorbidities on OA pathology Mechanisms of pain ■■ Relationship of structural pathology and pain ■■ Sources of pain in OA and how they might be targeted Treatment strategies ■■ Individualized or pathology-targeted therapy Early OA ■■ What is early OA and what determines the evolution to manifestations of the disease? Predictors of progression ■■ Studies of foot OA ■■ Performance metrics of imaging techniques and biomarkers Abbreviation: OA, osteoarthritis.
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS priority also ought to be given to better characterizing human loading during activity as any attempts at correcting mechanopathology will fail as long as the actual in vivo focal loads are not precisely characterized. The EULAR committee recommended that the OA research portfolio be expanded to include foot OA. Given the increased prevalence of OA in ageing populations, shoulder and ankle OA should be added to this list, joints believed in the past to be rarely affected by OA. Furthermore, improved understanding of the relationship between spinal disease and peripheral OA is needed as insights from one of these fields in terms of disease pathogenesis or treatment could inform the other.
‘‘
Given the magnitude of the problem of OA, why does it remain unsolved?
’’
Other recommendations from the committee, unfortunately, might be less likely to yield insights. The research community is migrating quickly to the study of those with early OA; however, by the time individuals present to physicians with knee or hip pain, structural abnormalities seen by MRI have probably been present for a long period even when radiographs were normal.4 Even this ‘early’ disease presentation might be too late for successful structural modification. Other strategies could include prevention of disease in as yet unaffected joints in a person who has initial symptoms in only one joint6 and asking persons known to be at risk of OA to adopt preventive strategies. This latter approach might work if persons with early OA had an initial bout of joint pain that was, for them, a ‘teachable moment’. Given the poor diagnostic performance of single or multiple biochemical markers in blood and urine in patients with OA versus controls, 7 it is unlikely that biomarker studies of blood or urine will yield diagnostic tests for OA. This caveat is true, in part, because these biomarkers emanate from multiple different sites in the body and characterizing one or two joints as having disease on the basis of a ‘flood’ of markers from multiple joints is not terribly valuable. Biochemical markers might ultimately be valuable as measures of treatment response
or as indicators of the burden of disease (discussed elsewhere7). On the other hand, MRI findings could be used to offer sensitive information about the degree of structural abnormalities and provide information on treatable abnormalities. Lastly, the committee advocated more studies on the progression of OA.1 Ideally, a risk factor for progression would be a modifiable target for treatment. However, there have been two systemic reviews of a large number of studies on OA progression (for instance by Chapple et al.8), and both have concluded that there are few, if any, consistently identified risk factors for dis ease progression in OA; for example, obesity has not been shown to consistently increase the risk of disease progression, although it does increase the risk of incidence in almost all studies examined. Why are risk factors for OA disease progression so hard to identify? As noted in recent work about the obesity paradox in heart disease (obesity ironically decreases the risk of subsequent events in those with heart disease), there are daunting methodological challenges to studying risk factors for disease progression. These challenges have gone under different names in the medical9 and arthritis literature,10 including index event bias and collider selection bias. The main idea is that among persons with disease, all have to have had risk factors for disease incidence to get disease and, thus, also have risk factors for disease progression. Identifying risk factors for progression is only possible if the disease sample studied includes some persons who have no risk factors for progression, but that is never the case. Differentiating the effects of these factors on the risk of progression is terribly difficult; it is easier to study risk factors for disease incidence because these studies evaluate a mixed population containing some persons without disease risk factors. The only easily identifiable risk factors for OA progression are risk factors that develop as a variable consequence of disease such as malalignment, which has been shown to be a risk factor for progression in at least one systematic review. 8 The presence of this bias suggests that only incidence studies or studies of very early disease will provide useful information about risk factors for OA progression and that pursuing large-scale
2 | ADVANCE ONLINE PUBLICATION
studies of risk factors for disease progression will probably not be fruitful in identifying new treatment targets. In summary, motivated by our lack of success in developing nonsurgical treatments for OA and the increasing burden this disease poses to our society and our patients, a EULAR committee has put forward new priorities for research that, if followed, might finally begin to yield treatments that delay progression or prevent disease. Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Suite 200, 650 Albany Street, Boston, MA 02118, USA. [email protected] Acknowledgements D.T.F. is supported by NIH grant AR47785. Competing interests The author acts as a consultant for Zimmer Knee Creations. 1.
Conaghan, P. G., Kloppenburg, M., Schett, G. & Bijlsma, J. W. Osteoarthritis research priorities: a report from a EULAR ad hoc expert committee. Ann. Rheum. Dis. http://dx.doi.org/ 10.1136/annrheumdis-2013-204660. 2. Cibere, J. et al. Association of clinical findings with pre-radiographic and radiographic knee osteoarthritis in a population-based study. Arthritis Care Res. (Hoboken) 62, 1691–1698 (2010). 3. Loeser, R. F. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 17, 971–979 (2009). 4. Sharma, L. et al. Significance of preradiographic MRI lesions in persons at higher risk for knee osteoarthritis. Arthritis Rheum. http://dx.doi.org/10.1002/art.38611. 5. Mangiapani, D. S. et al. Inhibition of Interleukin‑1 prevents post-traumatic arthritis following articular fracture in the mouse knee [abstract 711]. Presented at the ORS 2012 Annual Meeting. 6. Jones, R. K. et al. A new approach to prevention of knee osteoarthritis: reducing medial load in the contralateral knee. J. Rheumatol. 40, 309–315 (2013). 7. Felson, D. T. The current and future status of biomarkers in osteoarthritis. J. Rheumatol. (in press). 8. Chapple, C. M., Nicholson, H., Baxter, G. D. & Abbott, J. H. Patient characteristics that predict progression of knee osteoarthritis: a systematic review of prognostic studies. Arthritis Care Res. (Hoboken) 63, 1115–1125 (2011). 9. Dahabreh, I. J. & Kent, D. M. Index event bias as an explanation for the paradoxes of recurrence risk research. JAMA 305, 822–823 (2011). 10. Zhang, Y. et al. Methodologic challenges in studying risk factors for progression of knee osteoarthritis. Arthritis Care Res. (Hoboken) 62, 1527–1532 (2010).
www.nature.com/nrrheum © 2014 Macmillan Publishers Limited. All rights reserved
